Aβ-damaged neural stem cells migration and differentiation through Wnt3a/β-catenin pathway: Protective effects of 17β-E2.

Alzheimer's disease (AD) is a widespread central nervous system degenerative disease in the elderly population. This study aims to uniquely targets this sex-specific vulnerability by investigating the effects of 17β-E2 on the differentiation and migration capabilities of Aβ-damaged NSCs and its potential mechanisms-a critical gap for female-focused AD therapies. Primary NSCs isolated from neonatal SD rats were treated with Aβ25-35 (60 μM) to mimic AD pathology, followed by 17β-E2 (100 nM) with or without BX795 (a Wnt3a/β-catenin inhibitor). Results showed that Aβ significantly suppressed Wnt3a, LRP6, and β-catenin mRNA/protein levels while increasing GSK-3β expression. 17β-E2 treatment reversed these effects, enhancing phosphorylated GSK-3β (Ser9) and β-catenin, which were abolished by BX795. Transwell assays demonstrated that 17β-E2 rescued Aβ-damaged migration deficits, accompanied by elevated p-MLC and Cdc42 protein levels. Furthermore, 17β-E2 promoted neuronal differentiation, increasing MAP2 + and βIII-tubulin + cells with enhanced dendritic complexity, whereas BX795 counteracted these benefits. These findings indicate that 17β-E2 mitigates Aβ-damaged NSCs dysfunction by activating the Wnt3a/β-catenin pathway via GSK-3β phosphorylation, highlighting its therapeutic potential for AD by enhancing neurogenesis and NSC mobility.